Severe ulcerative colitis (UC) is a potentially life-threatening disease with a potential colorectal cancer (CRC) risk. The aim of this study was to explore the relationship between transcriptomic ...and genome-wide DNA methylation profiles in a well-stratified, treatment-naïve severe UC patient population in order to define specific epigenetic changes that could be responsible for the grade of disease severity. Mucosal biopsies from treatment-naïve severe UC patients (n = 8), treatment-naïve mild UC (n = 8), and healthy controls (n = 8) underwent both whole transcriptome RNA-Seq and genome-wide DNA bisulfite- sequencing, and principal component analysis (PCA), cell deconvolutions and diverse statistical methods were applied to obtain a dataset of significantly differentially expressed genes (DEGs) with correlation to DNA methylation for severe UC. DNA hypo-methylation correlated with approximately 80% of all DEGs in severe UC when compared to mild UC. Enriched pathways of annotated hypo-methylated genes revealed neutrophil degranulation, and immuno-regulatory interactions of the lymphoid system. Specifically, hypo-methylated anti-inflammatory genes found for severe UC were IL10, SIGLEC5, CD86, CLMP and members of inflammasomes NLRP3 and NLRC4. Hypo-methylation of anti-inflammatory genes during severe UC implies an interplay between the epithelium and lamina propria in order to mitigate inflammation in the gut. The specifically DNA hypo-methylated genes found for severe UC can potentially be useful biomarkers for determining disease severity and in the development of new targeted treatment strategies for severe UC patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
DNA methylation has been implied to play a role in the immune dysfunction associated with inflammatory bowel disease (IBD) and the disease development of ulcerative colitis (UC). Changes of the DNA ...methylation and correlated gene expression in patient samples with inactive UC might reveal possible regulatory features important for further treatment options for UC. Targeted bisulfite sequencing and whole transcriptome sequencing were performed on mucosal biopsies from patients with active UC (UC, n = 14), inactive UC (RM, n = 20), and non-IBD patients which served as controls (NN, n = 11). The differentially methylated regions (DMRs) were identified by DMRseq. Correlation analysis was performed between DMRs and their nearest differentially expressed genes (DEGs). Principal component analysis (PCA) was performed based on correlated DMR regulated genes. DMR regulated genes then were functional annotated. Cell-type deconvolutions were performed based on methylation levels. The comparisons revealed a total of 38 methylation-regulated genes in inactive UC that are potentially regulated by DMRs (correlation p value < 0.1). Several methylation-regulated genes could be identified in inactive UC participating in IL-10 and cytokine signalling pathways such as IL1B and STAT3. DNA methylation events in inactive UC seem to be fine-tuned by the balancing pro- and anti- inflammatory pathways to maintain a prevailed healing process to restore dynamic epithelium homeostasis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Long non-coding RNAs (lncRNAs) have been shown to play a role in the pathogenesis of ulcerative colitis (UC). Although epigenetic processes such as DNA methylation and lncRNA expression are well ...studied in UC, the importance of the interplay between the two processes has not yet been fully explored. It is, therefore, believed that interactions between environmental factors and epigenetics contribute to disease development. Mucosal biopsies from 11 treatment-naïve UC patients and 13 normal controls were used in this study. From each individual sample, both whole-genome bisulfite sequencing data (WGBS) and lncRNA expression data were analyzed. Correlation analysis between lncRNA expression and upstream differentially methylated regions (DMRs) was used to identify lncRNAs that might be regulated by DMRs. Furthermore, proximal protein-coding genes associated with DMR-regulated lncRNAs were identified by correlating their expression. The study identified UC-associated lncRNAs such as MIR4435-2HG, ZFAS1, IL6-AS1, and Pvt1, which may be regulated by DMRs. Several genes that are involved in inflammatory immune responses were found downstream of DMR-regulated lncRNAs, including SERPINB1, CCL18, and SLC15A4. The interplay between lncRNA expression regulated by DNA methylation in UC might improve our understanding of UC pathogenesis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The study aimed to identify common differentially expressed lncRNAs from manually curated ulcerative colitis (UC) gene expression omnibus (GEO) datasets. Nine UC transcriptomic datasets of clearly ...annotated human colonic biopsies were included in the study. The datasets were manually curated to select active UC samples and controls. R packages geneknitR, gprofiler, clusterProfiler were used for gene symbol annotation. The R EdgeR package was used to analyze differential expression. This resulted in a total of nineteen lncRNAs that were differentially expressed in at least three datasets of the nine GEO datasets. Several of the differentially expressed lncRNAs found in UC were associated with promoting colorectal cancer (CRC) through regulating gene expression, epithelial to mesenchymal transition (EMT), cell cycle progression, and by promoting tumor proliferation, invasion, and migration. The expression of several lncRNAs varied between disease states and tissue locations within the same disease state. The identified differentially expressed lncRNAs may function as general markers for active UC independent of biopsy location, age, gender, or treatment, thereby representing a comparative resource for future comparisons using available GEO UC datasets.
In jawed vertebrates, two major T cell populations have been characterized. They are defined as α/β or γ/δ T cells, based on the expressed T cell receptor. Salmonids (family
) include two key teleost ...species for aquaculture, rainbow trout (
) and Atlantic salmon (
which constitute important models for fish immunology and important targets for vaccine development. The growing interest to decipher the dynamics of adaptive immune responses against pathogens or vaccines has resulted in recent efforts to sequence the immunoglobulin (IG) or antibodies and T cell receptor (TR) repertoire in these species. In this context, establishing a comprehensive and coherent locus annotation is the fundamental basis for the analysis of high-throughput repertoire sequencing data. We therefore decided to revisit the description and annotation of TRA/TRD locus in Atlantic salmon and two strains of rainbow trout (Swanson and Arlee) using the now available high-quality genome assemblies. Phylogenetic analysis of functional TRA/TRD V genes from these three genomes led to the definition of 25 subgroups shared by both species, some with particular feature. A total of 128 TRAJ genes were identified in
, the majority with a close counterpart in
. Analysis of expressed TRA repertoire indicates that most TRAV gene subgroups are expressed at mucosal and systemic level. The present work on TRA/TRD locus annotation along with the analysis of TRA repertoire sequencing data show the feasibility and advantages of a common salmonid TRA/TRD nomenclature that allows an accurate annotation and analysis of high-throughput sequencing results, across salmonid T cell subsets.
Abstract
Background
This study addresses whether existing specific transcriptional profiles can improve and support the current status of the definition of ulcerative colitis (UC) remission apart ...from the existing endoscopic, histologic, and laboratory scoring systems. For that purpose, a well-stratified UC patient population in remission was compared to active UC and control patients and was investigated by applying the next-generation technology RNA-Seq.
Methods
Mucosal biopsies from patients in remission (n = 14), patients with active UC (n = 14), and healthy control patientss (n = 16) underwent whole-transcriptome RNA-Seq. Principal component analysis, cell deconvolution methods, gene profile enrichment, and pathway enrichment methods were applied to define a specific transcriptional signature of UC in remission.
Results
Analyses revealed specific transcriptional signatures for UC in remission with increased expression of genes involved in O-glycosylation (MUC17, MUC3A, MUC5AC, MUC12, SPON1, B3GNT3), ephrin-mediated repulsion of cells (EFNB2E, EFNA3, EPHA10, EPHA1), GAP junction trafficking (TUBA1C, TUBA4A, TUBB4B, GJB3, CLTB), and decreased expression of several toll-like receptors (TLR1, TLR3, TLR5, TLR6).
Conclusions
This study reveals specific transcriptional signatures for remission. Partial restoration and improvement of homeostasis in the epithelial mucus layer and revival of immunological functions were observed. A clear role for bacterial gut flora composition can be implied. The results can be useful for the development of treatment strategies for UC in remission and may be useful targets for further investigations aiming to predict the outcome of UC in the future.
Specific transcriptional signatures for ulcerative colitis in remission reveal that partial restoration and improvement of the epithelial mucus layer and revival of immunological functions in the mucus layer are endorsed by the expression of protective genes. In addition, a clear role for bacterial gut flora composition can be implied.
Here we explored the role of interleukin-1β (IL-1β) repressor cytokine, IL-1 receptor antagonist (IL-1rn), in both healthy and abnormal hematopoiesis. Low IL-1RN is frequent in acute myeloid leukemia ...(AML) patients and represents a prognostic marker of reduced survival. Treatments with IL-1RN and the IL-1β monoclonal antibody canakinumab reduce the expansion of leukemic cells, including CD34
progenitors, in AML xenografts. In vivo deletion of IL-1rn induces hematopoietic stem cell (HSC) differentiation into the myeloid lineage and hampers B cell development via transcriptional activation of myeloid differentiation pathways dependent on NFκB. Low IL-1rn is present in an experimental model of pre-leukemic myelopoiesis, and IL-1rn deletion promotes myeloproliferation, which relies on the bone marrow hematopoietic and stromal compartments. Conversely, IL-1rn protects against pre-leukemic myelopoiesis. Our data reveal that HSC differentiation is controlled by balanced IL-1β/IL-1rn levels under steady-state, and that loss of repression of IL-1β signaling may underlie pre-leukemic lesion and AML progression.
Ulcerative colitis UC is a chronic inflammatory disease that effects the gastrointestinal tract and is considered one of the most prominent and common forms of inflammatory bowel disease IBD. This ...study aimed to define and describe the entire transcriptomic landscape in a well-stratified, treatment-naïve UC patient population compared with control patients by using next-generation technology, RNA-Seq.
Mucosal biopsies from treatment-naïve UC patients n = 14, and healthy controls n = 16 underwent RNA-Seq. Principal component analysis PCA, cell deconvolution methods, and diverse statistical methods were applied to obtain and characterise a dataset of significantly differentially expressed genes DEGs.
Analyses revealed 1480 significantly DEGs in treatment-naïve UC when compared with controls. Cell populations of monocytes, T cells, neutrophils, B cells/ lymphoid cells, and myeloid cells were increased during inflammation, whereas the fraction of epithelial cells were reduced in UC, which is reflected by the DEGs; 79 DEGs were identified as IBD susceptibility genes, and 58 DEGs were expressed in a gender-specific manner. MUC5B, REG3A, DEFA5, and IL33 might be considered as colorectal cancer CRC risk factors following UC in males. AQP9 together with CLDN2 may have a role regulating tissue-specific physiological properties in tight junctions in UC. An additional functional role for AQP9 in the synthesis and/or the function of mucus can be implied.
This study reveals new potential players in UC pathogenesis in general, and provides evidence for a gender-dependent pathogenesis for UC. These results can be useful for the development of personalised treatment strategies for UC in the future.
Background
In ulcerative colitis (UC), the molecular mechanisms that drive disease development and patient response to therapy are not well understood. A significant proportion of patients with UC ...fail to respond adequately to biologic therapy. Therefore, there is an unmet need for biomarkers that can predict patients’ responsiveness to the available UC therapies as well as ascertain the most effective individualised therapy. Our study focused on identifying predictive signalling pathways that predict anti-integrin therapy response in patients with UC.
Methods
We retrieved and pre-processed two publicly accessible gene expression datasets (GSE73661 and GSE72819) of UC patients treated with anti-integrin therapies: (1) 12 non-IBD controls and 41 UC patients treated with Vedolizumab therapy, and (2) 70 samples with 58 non-responder and 12 responder UC patient samples treated with Etrolizumab therapy without non-IBD controls. We used a diffusion-based signalling model which is mainly focused on the T-cell receptor signalling network. The diffusion model uses network connectivity between receptors and transcription factors.
Results
The network diffusion scores were able to separate VDZ responder and non-responder patients before treatment better than the original gene expression. On both anti-integrin treatment datasets, the diffusion model demonstrated high predictive performance for discriminating responders from non-responders in comparison with ‘nnet’. We have found 48 receptor-TF pairs identified as the best predictors for VDZ therapy response with AUC ≥ 0.76. Among these receptor-TF predictors pairs, FFAR2-NRF1, FFAR2-RELB, FFAR2-EGR1, and FFAR2-NFKB1 are the top best predictors. For Etrolizumab, we have identified 40 best receptor-TF pairs and CD40-NFKB2 as the best predictor receptor-TF pair (AUC = 0.72). We also identified subnetworks that highlight the network interactions, connecting receptors and transcription factors involved in cytokine and fatty acid signalling. The findings suggest that anti-integrin therapy responses in cytokine and fatty acid signalling can stratify UC patient subgroups.
Conclusions
We identified signalling pathways that may predict the efficacy of anti-integrin therapy in UC patients and personalised therapy alternatives. Our results may lead to the advancement of a promising clinical decision-making tool for the stratification of UC patients.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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